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Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE253033 | GEO | 2024/12/07

REPOSITORIES: GEO

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Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs [RNA-Seq]

Project description:Epigenetic control of cell type is a critical determinant in cell type stability and permissive differentiation. However, the epigenetic control mechanisms are not well understood. Here, we explore the epigenetic control of the conversion of primed mouse EpiSCs to naïve mouse ESCs as a mimic for early stages of embryonic development. Whilst the conversion of naïve to primed state is relatively permissive and mimics a normal developmental program, the reverse process, primed to naïve is inefficient in the absence of transgenes, which suggests the presence of potent epigenetic barriers that resist this artificial dedifferentiation. Here, we identify the histone acetylation reader BRD8 as a one-way barrier that blocks the conversion of primed to naïve cells. BRD8 works by maintaining histone acetylation on promoters and transcribed gene bodies and it’s absence promotes the formation of heterochromatin.

2024-12-08 | GSE253031 | GEO

Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs [ChIP-Seq]

2024-12-08 | GSE253030 | GEO

Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs [ATAC-Seq]

2024-12-08 | GSE253029 | GEO

Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs

Project description:Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs

| PRJNA1063672 | ENA

Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs [RNA-Seq]

Project description:Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs [RNA-Seq]

| PRJNA1063676 | ENA

Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs [ChIP-Seq]

Project description:Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs [ChIP-Seq]

| PRJNA1063677 | ENA

Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs [ATAC-Seq]

Project description:Epigenetic modulation through BRD8 impairs conversion of primed EpiSCs to naïve ESCs [ATAC-Seq]

| PRJNA1063678 | ENA

Regulation of pluripotency and self- renewal of ESCs through epigenetic-threshold modulation and mRNA pruning.

Project description:Embryonic stem cell (ESC) pluripotency requires bivalent epigenetic modifications of key developmental genes regulated by various transcription factors and chromatin-modifying enzymes. How these factors coordinate with one another to maintain the bivalent chromatin state so that ESCs can undergo rapid self-renewal while retaining pluripotency is poorly understood. We report that Utf1, a target of Oct4 and Sox2, is a bivalent chromatin component that buffers poised states of bivalent genes. By limiting PRC2 loading and histone 3 lysine-27 trimethylation, Utf1 sets proper activation thresholds for bivalent genes. It also promotes nuclear tagging of messenger RNAs (mRNAs) transcribed from insufficiently silenced bivalent genes for cytoplasmic degradation through mRNA decapping. These opposing functions of Utf1 promote coordinated differentiation. The mRNA degradation function also ensures rapid cell proliferation by blocking the Myc-Arf feedback control. Thus, Utf1 couples the core pluripotency factors with Myc and PRC2 networks to promote the pluripotency and proliferation of ESCs.

| S-EPMC3575637 | biostudies-literature

BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.

Project description:Inhibition of the tumour suppressive function of p53 (encoded by TP53) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)-the most common and deadly adult brain malignancy1,2. Thus, how p53-mediated tumour suppression is countered in TP53 wild-type (TP53WT) GBM is unknown. Here we describe a GBM-specific epigenetic mechanism in which the chromatin regulator bromodomain-containing protein 8 (BRD8) maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex. This mechanism causes a repressive chromatin state that prevents transactivation by p53 and sustains proliferation. Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility and engages p53 transactivation. This in turn enforces cell cycle arrest and tumour suppression in TP53WT GBM. In line with these findings, BRD8 is highly expressed with H2AZ in proliferating single cells of patient-derived GBM, and is inversely correlated with CDKN1A, a canonical p53 target that encodes p21 (refs. 3,4). This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades. Moreover, targeting the bromodomain of BRD8 may be a promising therapeutic strategy for patients with TP53WT GBM.

| S-EPMC10189659 | biostudies-literature

Project description:Predominant transcriptional subnetworks called Core, Myc, and PRC modules have been shown to participate in preservation of the pluripotency and self-renewality of embryonic stem cells (ESCs). Epiblast stem cells (EpiSCs) are another cell type that possesses pluripotency and self-renewality. However, the roles of these modules in EpiSCs have not been systematically examined to date. Here, we compared the average expression levels of Core, Myc, and PRC module genes between ESCs and EpiSCs. EpiSCs showed substantially higher and lower expression levels of PRC and Core module genes, respectively, compared with those in ESCs, while Myc module members showed almost equivalent levels of average gene expression. Subsequent analyses revealed that the similarity in gene expression levels of the Myc module between these two cell types was not just overall, but striking similarities were evident even when comparing the expression of individual genes. We also observed equivalent levels of similarity in the expression of individual Myc module genes between induced pluripotent stem cells (iPSCs) and partial iPSCs that are an unwanted byproduct generated during iPSC induction. Moreover, our data demonstrate that partial iPSCs depend on a high level of c-Myc expression for their self-renewal properties.

| S-EPMC3873369 | biostudies-literature

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